Pathways to psychosis: Investigating environmental, cognitive and genetic mechanisms underlying development of psychotic experiences in young adults

Schizophrenia is a severe psychiatric disorder that imposes a substantial burden on sufferers and their families, and is one of the leading causes of disability worldwide. Although treatments for schizophrenia exist there is a pressing need for more effective treatments and for interventions to prevent people from developing this disorder.

Schizophrenia is characterised by hallucinations (for example hearing voices) and delusions (for example an irrational belief that people are plotting to kill you). These are called psychotic experiences, and whilst schizophrenia affects about 1% of the population over the course of their lives, psychotic experiences occur much more commonly, affecting about 5% of adolescents and young adults. Although for most people these experiences are short lived and resolve completely, for some they persist, and may develop over time into a psychotic illness such as schizophrenia.

We aim to study the development of psychotic experiences from childhood through early adulthood to understand more about what causes these to develop, and what factors lead to recovery from these, or conversely, to deterioration and progression to a psychotic illness. We are particularly interested in examining the role of: i) social adversity during childhood and adolescence, characterised for example by childhood maltreatment or repeated victimization from bullying, and ii) cannabis use, on increasing the risk of developing psychotic experiences.
Social adversity and cannabis use can cause abnormalities in regulation of dopamine, an important neurotransmitter in the brain. This is of particular interest as there is very good evidence that increased dopamine activity in a specific brain pathway is a key biological abnormality underlying schizophrenia.

However, whilst there is good evidence of dopamine abnormalities underlying schizophrenia, it is not known how having too much dopamine can lead to someone hearing a voice that isn't there, or developing a belief that someone is plotting to kill them. Studies in cognitive neuroscience go some way to explaining this by demonstrating that altered dopamine function can affect how people perceive stimuli in their environment, and the inferences that they make about these events. For example, people with schizophrenia are more likely to interpret unimportant background stimuli as having important personal relevance, reach decisions based on insufficient evidence, and misattribute self-generated thoughts or speech as coming from an external source.

We aim to study whether abnormalities on cognitive tests of perception and inference are associated with psychotic experiences in young adults, and whether experiences of social adversity and cannabis use are also associated with deficits in these cognitive tests. This work can provide a model whereby social adversity or cannabis can lead to psychotic experiences through effects on perception and inference (via altered dopamine function). This work is important because cognitive processes influencing perception and inference are modifiable, and therefore evidence that they play a role in developing psychotic experiences will prioritize these as potential targets for psychological interventions to prevent people from developing schizophrenia.

Furthermore, although genetic effects play a critical role in determining risk of developing schizophrenia it is not known how this risk is expressed during development from childhood through early adulthood. We will examine how genetic risk for schizophrenia affects a broad range of psychopathology as well as intellectual ability and performance on cognitive tests of perception and inference. By combining work on genetic, psychological and social mechanisms we will increase our understanding of the pathways leading to development of psychotic experiences, to help inform interventions for treatment and prevention of schizophrenia.

This proposal aims to examine the development of psychotic experiences, at-risk mental states and psychotic disorder from childhood through to early adulthood in the general population, and to investigate social-environmental, cognitive and genetic mechanisms underlying this. We will measure psychotic outcomes in participants of the population-based ALSPAC birth cohort when they are age 24-25, a critical period as this is the peak age of incidence for schizophrenia. ALSPAC has a wealth of detailed information already available on the cohort participants including data from semi-structured interviews of psychotic experiences during childhood and adolescence that will allow us to track these experiences during development and study their impact on functioning and transition into psychotic disorder during early adulthood.

We will also examine the effects of social adversity and cannabis use on trajectories of psychotic experiences, and study how deficits in cognitive processes relating to perception and inference relate both to psychotic experiences in early adulthood, and to earlier experiences of social adversity and cannabis use. This work can inform us as to how these environmental exposures lead to development of psychotic phenomena, and help identify targets for interventions. We will also examine how genetic risk for schizophrenia, indexed by a composite measure of common alleles conferring increased risk of this disorder, is manifest phenotypically during development from childhood through early adulthood in a population-based sample, including expression of risk through cognitive processes relating to perception and inference. To address these questions we will use appropriate statistical techniques including structural equation models and mixture modeling techniques to examine changes in repeated measures over time, marginal structural models to deal with time-varying confounding, and multiple imputation to address issues relating to attrition.

The aim of this research is to understand more about the development of psychotic experiences from childhood through to young adulthood, and about the bio-psycho-social mechanisms underlying this. The personal and economic burden of psychotic disorders is substantial, and there is a pressing need for more effective therapies to treat psychosis, and to prevent transition in high-risk individuals. This research project is focused on questions that will have an impact beyond the academic environment, with other beneficiaries described below.

Service users and families
Understanding more about the cognitive mechanisms that translate biological abnormalities into the experience of hearing voices or development of delusional beliefs is critical to aid the development of effective psychological treatments for psychosis. Identifying relevant cognitive processes to target for such interventions will benefit patients with psychotic experiences by improving outcomes and reducing disability across a broad spectrum of clinical diagnoses. This will also benefit the pharmaceutical industry as it will inform the development of new markers for use as surrogate endpoints in experimental medicine and early phase clinical trials. A better understanding of how psychotic experiences develop will also benefit patients and their families by reducing the stigma associated with psychotic disorders.

Young people in the community
Identifying modifiable dysfunctional cognitive processes involved in the aetiology of psychosis will also inform preventive interventions. The potential for such interventions to be applied at a population (for example school) level rather than targeting high-risk individuals will confer a greater public health impact on reducing psychosis and other adverse outcomes that result from dysfunctional cognitive processes. This is particularly attractive as it means that young people who are not engaged in clinical services will also benefit, whilst applying interventions at a broad level also reduces stigma associated with targeted approaches. In the longer term this will benefit young people by reducing their risk of transition into clinical disorder. Improving cognitive biases will also improve relationships and social and occupational functioning, thus having economic impact as well as improving quality of life. A greater understanding of long-term effects of victimization on development of psychosis will enhance the drive to target and reduce the occurrence of such behaviour in schools and work places. This will confer benefits to all individuals within such organisations and lead to benefits in relation to other (non-psychotic) aspects of mental health and well-being, as well as improving quality of life.

Public sector, policy and practice
Our work previously on the relationship between cannabis use and psychosis has been presented to government advisory boards and contributed to debates about policy. It has also been used to inform the public about the possible mental health consequences of use of this drug. Through engagement with the young people involved in this study, and with the wider public (as detailed in the Pathways to Impact), the work from this project can benefit members of the general public by providing information that can help them make informed decisions about use of cannabis, and about their level of risk if, for example, they have an increased inherited risk of psychosis. This research will increase the quality of information contributing to the debate about the effects of cannabis use amongst policy-makers and the wider public.
Understanding the risk of transition from psychotic experiences to disorder, and factors influencing this will benefit practitioners who are often faced with difficult questions about risk prediction when robust estimates from large population-based samples are not available. Such knowledge can help them advise high-risk individuals appropriately.